Design, Synthesis and Biological Evaluation of Phenylglyoxamide- and Benzothiazole-Based Small Molecular Peptidomimetics as Antibacterial Agents

The rapid emergence and development of antibacterial resistance is a major global threat to public health. There is an urgent need for the development of antibacterial agents with novel therapeutic strategy to tackle the increasing incidence of antibacterial resistance. In recent years, antimicrobial peptides (AMPs) and their synthetic mimics have been under the spotlight of the development of a novel class of antibiotics to combat antibiotic resistance. This research project focused on the utilisation of phenylglyoxamide and benzothiazole scaffolds in the development of antimicrobial peptidomimetics. The synthesis of phenylglyoxamide-based peptidomimetics was achieved via the ring-opening reactions of N-sulfonylisatins with primary amines followed by salt formation. Minimum inhibitory concentrations (MIC) of the peptidomimetics against different bacterial strains were determined to assess their antibacterial activity. Structure-activity relationship (SAR) studies revealed the inverse relationship between the alkylsulfonyl chain length and the bulkiness of the phenyl ring system for high antibacterial activity. The most active peptidomimetics exhibited high antibacterial activity with the lowest MIC to be 4, 16 and 63 μM against S. aureus, E. coli and P. aeruginosa, respectively. These peptidomimetics also showed significant biofilm disruption (up to 50%) and inhibition (up to 70%) against S. aureus at 2–4× MIC. In addition, terphenylglyoxamide-based peptidomimetics synthesised by the ring-opening reaction of N-acylisatins with amines and amino acid esters were evaluated for their quorum sensing inhibition (QSI) activity against P. aeruginosa MH602. The most potent peptidomimetic possessed high QSI activity of 82%, 65% and 53% at 250, 125 and 62.5 μM, respectively, with no bacterial growth inhibition. On the other hand, benzothiazole-based peptidomimetics were synthesised via the Jacobson method of cyclisation of phenylthioamides, followed by the installation of cationic groups. 2-Naphthyl and guanidinium hydrochloride as the hydrophobic and cationic groups, respectively, were important for high antibacterial activity of the peptidomimetics against both Gram-positive and Gram-negative bacteria. The most potent peptidomimetics against S. aureus, E. coli and P. aeruginosa possessed MIC values of 2, 16 and 32 μM, respectively. These active peptidomimetics inhibited 39% of S. aureus biofilm formation and disrupted 42% of preformed S. aureus biofilms at sub-MIC